Although an effective AIDS vaccine is the best hope for containing the world-wide AIDS epidemic, the failure of the T-cell-based Merck vaccine has highlighted our lacunae in knowledge about the correlates of vaccine protection. There is currently renewed emphasis on the necessity for more basic research on mechanisms of AIDS pathogenicity and development of therapeutic strategies in the nonhuman primate model. Natural hosts of the simian immunodeficiency virus (SIV) have co-evolved with the virus for millions of years and adapted to SIV in a way that disease progression does not occur or is markedly slowed down despite persistent viremia. Understanding mechanisms that allow nonpathogenicity in natural hosts is highly relevant for basic AIDS research and can expand the scope of AIDS vaccine research beyond the goal of achieving sterile protection, to developing additional novel therapeutic strategies. In recent studies we have shown that acute events following SIV infection in rhesus macaques (RM) differ from those occurring in the natural host sooty mangabeys (SM) with regards to the presence of CD4+ T lymphocyte apoptosis and increase in TNF- receptor associated apoptosis-inducing ligand (TRAIL) We hypothesize that increased TRAIL production leading to increased CD4+ T lymphocyte apoptosis initiates bystander T lymphocyte activation and is critical to the development of chronic immune activation and AIDS progression following pathogenic lentiviral infection. In this grant we propose to examine whether inhibition of TRAIL will result in alteration of the outcome of SIV infection in rhesus macaques. We also propose to perform a detailed examination of differences in the early host response to immunogens in SM and RM using a herpes simplex virus (HSV)-based vaccine approach expressing SIV immunogens. Our Specific Aims are: Specific Aim #1: Investigate the hypothesis that an acute increase in TRAIL production is a cardinal feature of pathogenic lentiviral infection and causally linked to induction of CD4+ T lymphocyte apoptosis and development of AIDS. Specific Aim #2: Determine whether sooty mangabey and rhesus macaque CD4+ T lymphocytes differ in their susceptibility to TRAIL-mediated apoptosis in the absence or presence of SIV infection. Specific Aim #3: Investigate differences in the early innate and adaptive host response to SIV immunogens in vaccinated sooty mangabeys and rhesus macaques.